Clinical Significance of Gene Amplification Studied in Human Neuroblastoma Xenografts: Relationship with Tumor Growth Rate, Chemotherapeutic Sensitivities and Levels of Neuron-Specific Enolase

Abstract

Tumor doubling time, sensitivity to chemotherapeutic agents and concentrations of neuron-specific enolase were studied in nine human neuroblastoma xenografts, in which amplifications of N-myc, clones 8 and G21 were known; N-myc was amplified in eight, clone 8 in five and clone G21 in four of these nine xenografts. Tumor doubling time was longest in one xenograft, TNB10, which lacks the amplification of either N-myc or clone 8 or G21 and shortest in TNB1 in which all three DNA sequences are amplified with a DNA rearrangement in clone 8. No correlations were found between genomic amplification of N-myc, clones 8 and G21 and effectiveness of five chemotherapeutic drugs tested, except for cis-platinum. cis-Platinum was found to be effective on all but the one xenograft, TNB 10, with the longest tumor doubling time. Concentration of neuron-specific enolase in tumor extract was lowest in TNB1 and correlated with the length of the tumor doubling time.

Effects of CPT‐11 (a unique DNA topoisomerase I inhibitor) on a highly malignant xeno‐transplanted neuroblastoma

“…Cytogenetic and molecular-biological investigations demonstrated that this xenograft showed an abnormal chromosome 1, a homogeneously staining resion (HSR) on chromosome 20, and 80-fold amplification of N-myc, 60-fold amplification of clone 8, and 100-fold amplification of clone G21 [21]. This xenograft was considered to be a representative of highly malignant human neuroblastomas with a short recorded tumor doubling time (4.8 days) [22]. A pilot chemosensitivity test showed that TNB9 is sensitive to cis-platinum but not to aclarubicin [22].…”

“…This xenograft was considered to be a representative of highly malignant human neuroblastomas with a short recorded tumor doubling time (4.8 days) [22]. A pilot chemosensitivity test showed that TNB9 is sensitive to cis-platinum but not to aclarubicin [22]. Effects of 15 other chemotherapentic agents on TNB9 are already known [ 18,191 according to the schedule of drug administration described below.…”

Accelerating development of high-risk neuroblastoma patient-derived xenograft models for preclinical testing and personalised therapy

“…Establishment of neuroblastoma PDX models from primary tumour samples was first reported over 25 years ago [19][20][21] and has been described in more recent accounts. [22][23][24][25][26][27][28] Herein, we demonstrate the feasibility of developing high-risk neuroblastoma PDX models at a high success rate from multiple sources of tumour-bearing patient materials at both diagnosis and relapse and from primary and metastatic tumour sites, and for the first time, residual tumour cells from cytogenetic analysis.…”

N-myc amplification and cell proliferation rate in human neuroblastoma

“…8,9 Recent investigations have shown that the proliferative activity of the tumour represents an important prognostic parameter in neuroblastoma, being significantly correlated with the clinical outcome of the disease. [10][11][12][13] Moreover, a study carried out in a series of neuroblastoma xenografts demonstrated that the only tumour without N-myc amplification had the longest doubling time, 14 indicating that N-myc amplification might produce faster cell proliferation.…”